Methods to improve adhesion of polymer coatings over stents

ABSTRACT

Methods are disclosed to improved adhesion of polymer coatings over polymer surfaces of stents which include plasma treatment, applying an adhesion promoting layer, surface treatments with solvents, and mechanical roughening techniques.

This is a divisional application of application Ser. No. 11/953,657filed on Dec. 10, 2007, now U.S. Pat. No. 7,998,524 which isincorporated by reference herein.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to adhesion of coatings for implantable medicaldevices composed of bioabsorbable polymers.

2. Description of the State of the Art

This invention relates to radially expandable endoprostheses, which areadapted to be implanted in a bodily lumen. An “endoprosthesis”corresponds to an artificial device that is placed inside the body. A“lumen” refers to a cavity of a tubular organ such as a blood vessel.

A stent is an example of such an endoprosthesis. Stents are generallycylindrically shaped devices, which function to hold open and sometimesexpand a segment of a blood vessel or other anatomical lumen such asurinary tracts and bile ducts. Stents are often used in the treatment ofatherosclerotic stenosis in blood vessels. “Stenosis” refers to anarrowing or constriction of the diameter of a bodily passage ororifice. In such treatments, stents reinforce body vessels and preventrestenosis following angioplasty in the vascular system. “Restenosis”refers to the reoccurrence of stenosis in a blood vessel or heart valveafter it has been treated (as by balloon angioplasty, stenting, orvalvuloplasty) with apparent success.

The treatment of a diseased site or lesion with a stent involves bothdelivery and deployment of the stent. “Delivery” refers to introducingand transporting the stent through a bodily lumen to a region, such as alesion, in a vessel that requires treatment. “Deployment” corresponds tothe expanding of the stent within the lumen at the treatment region.Delivery and deployment of a stent are accomplished by positioning thestent about one end of a catheter, inserting the end of the catheterthrough the skin into a bodily lumen, advancing the catheter in thebodily lumen to a desired treatment location, expanding the stent at thetreatment location, and removing the catheter from the lumen.

In the case of a balloon expandable stent, the stent is mounted about aballoon disposed on the catheter. Mounting the stent typically involvescompressing or crimping the stent onto the balloon. The stent is thenexpanded by inflating the balloon. The balloon may then be deflated andthe catheter withdrawn. In the case of a self-expanding stent, the stentmay be secured to the catheter via a constraining member such as aretractable sheath or a sock. When the stent is in a desired bodilylocation, the sheath may be withdrawn which allows the stent toself-expand.

The stent must be able to satisfy a number of mechanical requirements.First, the stent must be capable of withstanding the structural loads,namely radial compressive forces, imposed on the stent as it supportsthe walls of a vessel. Therefore, a stent must possess adequate radialstrength. Radial strength, which is the ability of a stent to resistradial compressive forces, is due to strength and rigidity around acircumferential direction of the stent. Radial strength and rigidity,therefore, may also be described as, hoop or circumferential strengthand rigidity.

Once expanded, the stent must adequately maintain its size and shapethroughout its service life despite the various forces that may come tobear on it, including the cyclic loading induced by the beating heart.For example, a radially directed force may tend to cause a stent torecoil inward. Generally, it is desirable to minimize recoil. Inaddition, the stent must possess sufficient flexibility to allow forcrimping, expansion, and cyclic loading. Longitudinal flexibility isimportant to allow the stent to be maneuvered through a tortuousvascular path and to enable it to conform to a deployment site that maynot be linear or may be subject to flexure. Finally, the stent must bebiocompatible so as not to trigger any adverse vascular responses.

The structure of a stent is typically composed of scaffolding thatincludes a pattern or network of interconnecting structural elementsoften referred to in the art as struts or bar arms. The scaffolding canbe formed from wires, tubes, or sheets of material rolled into acylindrical shape. The scaffolding is designed so that the stent can beradially compressed (to allow crimping) and radially expanded (to allowdeployment). A conventional stent is allowed to expand and contractthrough movement of individual structural elements of a pattern withrespect to each other.

Furthermore, it may be desirable for a stent to be biodegradable. Inmany treatment applications, the presence of a stent in a body may benecessary for a limited period of time until its intended function of,for example, maintaining vascular patency and/or drug delivery isaccomplished. Therefore, stents fabricated from biodegradable,bioabsorbable, and/or bioerodable materials such as bioabsorbablepolymers should be configured to completely erode only after theclinical need for them has ended.

Additionally, a medicated stent may be fabricated by coating the surfaceof either a metallic or polymeric scaffolding with a polymeric carrierthat includes an active or bioactive agent or drug. Polymericscaffolding may also serve as a carrier of an active agent or drug.Potential problems with therapeutic coatings for polymeric implantablemedical devices, such as stents, include insufficient toughness, slowdegradation rate, and poor adhesion.

SUMMARY OF THE INVENTION

Various embodiments of the present invention include a method ofimproving the adhesion of a polymer coating layer to a stent surfacecomprising: providing a stent formed from a substrate polymer; treatinga polymer surface of the stent with a fluid capable of swelling thesubstrate polymer, dissolving the substrate polymer, or both, whereinthe treating increases the roughness of the polymer surface; and forminga coating comprising coating polymer on the treated stent surface, theincreased surface roughness enhancing the adhesion of the coatingpolymer to the stent surface.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts a view of a stent.

FIG. 2A depicts a polymer surface before and after plasma treatment.

FIG. 2B is a cross-sectional view of a polymer over a plasma treatedsurface.

FIG. 2C depicts a stent mounted on a cone mandrel support.

FIG. 3 depicts a stent mounted on a cone mandrel support receiving asurface roughening treatment.

FIG. 4A depicts a stent roughening apparatus utilizing an agitatedparticle dispersion.

FIG. 4B depicts a stent luminal surface roughening apparatus utilizing abrush.

FIG. 4C depicts a stent abluminal surface roughening apparatus utilizinga brush.

FIG. 5 depicts a cross-section of a solvent roughened stent surface witha coating layer over a substrate.

FIG. 6A depicts a cross-section of a stent showing a coating materiallayer over a swollen surface polymer layer.

FIG. 6B depicts a cross-section of a stent polymer surface with acopolymer adhesion promoting layer over a substrate of the stent showingan interfacial region.

FIG. 6C depicts the cross-section of a stent surface with a drug-polymerlayer over a copolymer adhesion promoting layer disposed over asubstrate of the stent.

FIG. 6D depicts the cross-section of a stent with an adhesion promotinglayer disposed over the substrate and a therapeutic layer disposed overthe adhesion promoting layer.

DETAILED DESCRIPTION OF THE INVENTION

Various embodiments of the present invention include an implantablemedical device with a polymer surface that has been modified to improveadhesion between the surface and an applied coating. In someembodiments, the surface of the device is modified using a plasmatreatment, mechanical roughening, or treating the surface with solventsto etch the surface. Other embodiments are directed to an adhesionpromoting layer between the surface and a therapeutic layer. The variousembodiments will be discussed below, along with examples.

The polymeric surface may be a surface of a polymer coating disposedabove a substrate that can be composed of metal, polymer, ceramic, orother suitable material. Alternatively, the polymeric surface may be asurface of a polymeric substrate. “Above” a surface is defined as higherthan or over a surface measured along an axis normal to the surface, butnot necessarily in contact with the surface.

The present invention may be applied to implantable medical devicesincluding, but not limited to, self-expandable stents,balloon-expandable stents, stent-grafts, and grafts (e.g., aorticgrafts), and generally expandable tubular devices for various bodilylumen or orifices. A stent can have a scaffolding or a substrate thatincludes a pattern of a plurality of interconnecting structural elementsor struts. FIG. 1 depicts a view of an exemplary stent 100. Stent 100includes a pattern with a number of interconnecting structural elementsor struts 110. In general, a stent pattern is designed so that the stentcan be radially compressed (crimped) and radially expanded (to allowdeployment). The stresses involved during compression and expansion aregenerally distributed throughout various structural elements of thestent pattern. The variations in stent patterns are virtually unlimited.

In some embodiments, a stent may be fabricated by laser cutting apattern on a tube or a sheet rolled into a tube. Representative examplesof lasers that may be used include, but are not limited to, excimer,carbon dioxide, and YAG. In other embodiments, chemical etching may beused to form a pattern on a tube.

An implantable medical device can be made partially or completely from abiodegradable, bioabsorbable, bioerodable, biostable polymer, or acombination thereof. A polymer for use in fabricating an implantablemedical device can be biostable, bioabsorbable, biodegradable orbioerodable. Biostable refers to polymers that are not biodegradable.The terms biodegradable, bioabsorbable, and bioerodable are usedinterchangeably and refer to polymers that are capable of beingcompletely degraded and/or eroded when exposed to bodily fluids such asblood and can be gradually resorbed, absorbed, and/or eliminated by thebody. The processes of breaking down and absorption of the polymer canbe caused by, for example, hydrolysis, enzymolysis, oxidation, andmetabolic processes.

As indicated above, a medicated implantable medical device, such as astent, may be fabricated by coating the surface of a stent with a drug.For example, a device can have a coating including a drug dispersed in apolymeric carrier disposed over a substrate of the stent. Such a coatinglayer may be formed by applying a coating material to a substrate of animplantable medical device, such as a stent. The coating material can bea polymer solution and a drug dispersed in the solution. The coatingmaterial may be applied to the stent by immersing the stent in thecoating material, by spraying the material onto the stent, or by othermethods known in the art. The solvent in the solution is then removed,for example, by evaporation, leaving on the stent surfaces a polymercoating impregnated with the drug.

Stents are typically subjected to stress during use. “Use” includesmanufacturing, assembling (e.g., crimping a stent on balloon), deliveryof a stent through a bodily lumen to a treatment site, deployment of astent at a treatment site, and treatment after deployment. Both theunderlying scaffolding or substrate and the coating experience stressthat result in strain in the substrate and coating. In particular,localized portions of the stent's structure undergo substantialdeformation. For example, the apex regions of bending elements 130, 140,and 150 in FIG. 1 experience relatively high stress and strain duringcrimping, expansion, and after expansion of the stent.

As indicated above, a device may be composed in whole or in part ofmaterials that degrade, erode, or disintegrate through exposure tophysiological conditions within the body until the treatment regimen iscompleted. The device may be configured to disintegrate and disappearfrom the region of implantation once treatment is completed. The devicemay disintegrate by one or more mechanisms including, but not limitedto, dissolution and chemical breakdown. The duration of a treatmentperiod depends on the bodily disorder that is being treated. Forillustrative purposes only, in treatment of coronary heart diseaseinvolving use of stents in diseased vessels, the duration can be in arange from about a month to a few years. However, the duration istypically in a range from about six to twelve months. Thus, it isdesirable for polymer-based coatings and substrates of an implantablemedical device, such as a stent, to have a degradation time at or nearthe duration of treatment. Degradation time refers to the time for animplantable medical device to substantially or completely erode awayfrom an implant site.

Furthermore, polymer substrates and polymer-based coatings may beparticularly vulnerable to mechanical instability during use of a stent.Such mechanical instability for coatings can include fracture anddetachment from a substrate, for exampling, peeling. Some polymers maybe susceptible to such mechanical instability due to insufficienttoughness at high deformations. Additionally, detachment of coatings maybe due to poor adhesion of the polymer-based coating to the substrate oranother polymer layer. Therefore, polymer-based coatings are highlysusceptible to tearing or fracture, and/or detachment, especially atregions subjected to relatively high stress and strain. Thus, it isimportant for a polymer-based coating to have good adhesion with anunderlying layer or substrate and to have a high resistance todetachment in the range of deformations that occur during crimping,during deployment of a stent, and after deployment.

Accordingly, the following embodiments are directed to different methodsof increasing the adhesion of coatings to the substrate by altering thesurface of the substrate or by providing an adhesion promoting layer.

Surface Plasma Treatment

Certain embodiments of the invention are directed to treating a polymersurface of an implantable medical device prior to applying a coatinglayer to the device. The plasma treatment of the surface improves theadhesion of the coating layer applied to the plasma treated surface.

A plasma is a partially ionized gas containing ions, electrons, atomsand neutral species. Plasmas are formed when energy exceeding theionization energy of gaseous atoms/molecules is applied to them, therebycausing ionization. Ionization results in the formation of freeelectrons, ionic species, photons, and free radicals. Plasmas may becharacterized by the following variables: density of the neutralparticles, densities of electrons and ions, energy distributions, andthe degree of ionization.

To enable a gas to be ionized in a controlled and qualitative manner,the plasma formation is carried out under vacuum conditions. Inexemplary plasma formation processes, a vacuum vessel is first pumpeddown via rotary and roots blowers, sometimes in conjunction withhigh-vacuum pump, to a low to medium vacuum pressure in the range of10-2 to 10-3 mbar. The gas is then introduced into the vessel by meansof mass flow controllers and valves. Exemplary gases or mixtures ofgases for plasma treatment of polymers include, but are not limited to,oxygen, helium, argon, nitrous oxide, tetrafluoromethane, and air. Ahigh-frequency generator, for example, in the kHz, MHz, or microwaverange, can be then used to ionize the gas into a plasma.

In a low temperature plasma treating processes, a gas is ionized in avacuum (typically 10 to 1000 millitorr) which creates low temperatureand non-thermal equilibrium plasma. The temperature of the gas is about30 to 50° C. above ambient.

In exemplary embodiments, the energy for ionizing or activating energyin plasma treating can come from long or short radio waves ormicrowaves. Typically, 40-400 kHz is used at the lower end, 13.56 MHz inthe middle, and 2.54 GHz in the upper end. Most plasma treatments use13.56 MHz. The shorter the wavelength, the greater the ionization andthe more chemically active the gas becomes. In other exemplaryembodiments, a plasma can be formed by applying electrical energy,including direct current (DC) and alternating current (AC).

Plasma systems generally comprise five main components: the vacuumvessel, a pumping apparatus, a gas-introduction and gas-control system,an RF generator, and a microprocessor-based system controller. Variousoptional parts can then be added to adapt a base system to handleparticular applications or substrates, such as special barrels for smallpieces, modified electrode racks, or guiding systems for textiles orfibers. A wide range of equipment is available, from smallerlaboratory-scaled systems and custom-designed units to large textiletreaters.

A plasma includes highly reactive particles since due to the high energystate of such particles. Thus, in some embodiments, the reactiveparticles react with a polymer surface without little or no damage tothe bulk properties of the treated part of the surface. In exemplaryembodiments, the surface modification of a treated surface may belimited to an outermost region of 10 to 1000 Å of the substrate,although the region can be greater than 1000 Å. Below the surfacemodified region, the polymer can be unmodified by the plasma orsubstantially unmodified.

In certain embodiments of the present invention, a polymer surface of animplantable medical device is treated with a plasma to modify thesurface. In such embodiments, the treated surface is activated such thatthe treated surface is more reactive. “Activation” generally refers toincreasing the chemical reactivity of a surface. The activation by aplasma treatment may be due to the replacement of surface polymer groupswith chemical groups from the plasma. In these embodiments, during suchactivation, the plasma breaks down weak bonds in the polymer andreplaces them with highly reactive amino (—NH₂), carbonyl (C═O),carboxyl (—COOH), and hydroxyl groups (—OH).

Various kinds of polymer surfaces can be activated with a plasmatreatment. These include biodegradable polyesters, polyanhyrides, andpolyorthoesters. In general, the specific change in substratecharacteristics are determined by the type of chemical groupsincorporated into the surface.

FIG. 2A depicts a polymer surface 200 of a stent prior to plasmatreatment and activated polymer surface 201 after plasma treatment.Plasma treated polymer surface 201 includes an activated region 202having highly reactive functional groups. Such groups are capable ofchemical bonding to a selected polymer disposed over the activatedsurface. A region 203 below activated region 202 can be unmodified orsubstantially unmodified by the plasma treatment.

In some embodiments, the treatment of the polymer surface increases theadhesion of a polymer coating disposed over the treated surface. In suchembodiments, the coating polymer is capable of chemical bonding with thehighly reactive functional groups formed by the plasma. FIG. 2B depictsa polymer coating layer 204 disposed over activated region 202. Thereactive functional groups of activated region 202 chemically bond tocoating polymer of layer 204 in a region of layer 204 adjacent toactivated region 202.

The coating polymer can include various kinds of biodegradable polymersincluding, but not limited to, PLLA (poly(L-lactide), PDLA(poly(D,L-lactide), PCL (polycaprolactone), PDO (polydioxanone), and PGA(polyglycolide). The copolymers of the above-mentioned polymers caninclude random, alternating, or block copolymers. It is believed thatduring formation of a polymer coating over the activated surface, thecoating polymer can chemically bond to the active surface, therebyincreasing the adhesion of the coating polymer to the treated surface.The increased polarity of the activated surface can also increase theadhesion through non-covalent bonding. This includes hydrogen bonding,dipolar interactions, and London van der Waals forces.

Plasma treatment is particularly advantageous for surfacepolymer/coating polymer combinations in which the surface and coatingpolymer have a low miscibility or are immiscible. For miscible coatingpolymer/surface polymer combinations, during the coating process,surface and coating polymer can mix in a surface region. Such mixingenhances the adhesion of the coating polymer to the surface polymer.

Exemplary Embodiment

In certain embodiments, the stent substrate or surface polymer is asemi-crystalline biodegradable polymer. In such embodiments, thesemi-crystalline polymer may have Tg above human body temperature. Thecrystallinity may be at least 10%, 30% 50%, 60%, or greater than 60% byvolume. In such embodiments, the coating polymer can have a lowercrystallinity than the surface polymer or the coating polymer can beamorphous.

In an exemplary embodiment, the stent substrate polymer is PLLA and thecoating polymer is PDLA. PLLA is immiscible with PDLA since PLLA is asemi-crystalline polymer and PDLA is amorphous. The PLLA stent substrateis plasma treated to activate the PLLA surface to form reactive amino(—NH₂), carbonyl (C═O), carboxyl (—COOH), and hydroxyl groups (—OH) on asurface of the stent substrate. The plasma treatment of the PLLAsubstrate surface enhances the adhesion of the PDLA surface to thesubstrate.

In some embodiments, the plasma treatment can modify the crystallinityof a treated surface so that a surface region has lower crystallinity.Thus, the modified surface region may be miscible with a coating polymerhaving a lower crystallinity than an untreated surface polymer. As aresult, the adhesion of the coating polymer to the surface polymer canbe enhanced due to the increased miscibility of the polymer arising fromthe decreased cystallinity of the surface polymer. For example, plasmatreatment of a PLLA surface can form a surface region of lowercrystallinity that is miscible with a PDLA coating polymer.

In embodiments of plasma treatment, a stent can be disposed on a stentsupport positioned within the plasma vacuum chamber. The stent supportcan include various types of supports or mandrels known in the art usedfor spray coating stents. The mandrel can be designed so as to minimizecontact area of the stent with the support to reduce or eliminateuntreated areas of the stent surface. FIG. 2C depicts a schematicillustration of a stent 206 disposed on a cone mandrel support 205including a proximal support member 207, a distal support member 208 andcore wire 210 extending between the cone members. Proximal end 206A ofstent 206 is supported by cone member 207 and a distal end 206B of stent206 is supported by cone member 208. One or both of the cone supportmembers are affixed to rotatable fixture (not shown) that allowsrotation of stent 206 as shown by an arrow 209, thereby allowing a moreeven application of plasma treatment to stent 206.

In some embodiments, the mandrels may be made of Teflon or a metal suchas stainless steel. The fixture with the mandrel/stent assemblies isplaced in a Plasma Treater, such as a March Plasma C-Series PlasmaTreater (St. Petersburg, Fla.). The stents are treated using a workinggas in a plasma environment.

The working gas can be helium, argon, oxygen, carbon dioxide, nitrogen,nitrous oxide, ammonia, tetrafluoromethane, water vapor, air orcombinations thereof In some embodiments, a working gas is supplied at arate in the range of about 0.01 to 10 liters/minute. In furtherembodiments, the rate is 1 liter/minute. The gas rate is typicallydetermined by the size of the plasma chamber and specified by themanufacturer of the plasma treater.

In certain embodiments, the pressure of the plasma chamber may be in therange of about 10 to 1000 millitorr. In some embodiments, the pressureis 100 millitorr.

The Plasma Treater may supply power in the range of about 10 to 2000watts for about 10 to 600 seconds. Under certain embodiments, plasmaconditions of about 200 watts for approximately 150 seconds areexecuted. Power may be supplied from a high-frequency voltage source.

One feature of plasma treatment is its short cycle time, and adequatetreatment can be achieved in minutes. In some embodiments, longer plasmatreatment times can result in a higher levels of surface modificationwith new functional groups. Excessively long exposure can cause polymerdegradation and scission on the surface. Loose polymer fragments canthen adversely effect the adhesion of a subsequent coating layer. Thepower level must be adequate to ignite' or create the plasma byionization. Higher powers levels can create a more intense plasma with ahigher concentration of reactive species. This can also lead to moreenergetic photons in the UV and vacuum UV range. While this canfunctionalize the surface, it can also, if taken to extreme, createexcessive polymer degradation. In certain embodiments, the type of gasplays a critical role in the nature of the surface fuctionalization.Inert gases such as argon or helium do not actively bond to or becomeincorporated into the surface. They transfer energy by bombardment whichcreates free radicals at the surface and they also sputter the surfaceclean. Gases such as air, nitrogen, oxygen, nitrogen, water and CO₂break down to form reactive species which functionalize the polymersurface. For example, an oxygen plasma will result in the formation ofcarboxyl and hydroxyl groups on the surface. Careful treatment withammonia can lead to amino groups on the surface. Fluorine containinggases produce very reactive fluorine radicals which can etch and reactwith a very large range of surfaces.

Following removal of the stent from the plasma chamber, they may becoated with a polymer drug reservoir layer. In several embodiments, thecoating layer is applied within 1, 2, 6, or 12 hours of the plasmatreatment. The reactive groups created by plasma on the device surfacemay only be stable for a limited period which in some embodiments isseveral days. Additionally the reactive surface of a polymer chain canchange and evolve with time. Polymer chains formed within the bulkpolymer can diffuse to the surface and surface modified chains candiffuse into the bulk polymer.

The polymer coating may be applied to the substrate using any of thetechniques well known in the art, such as dipping or spraying thecoating material onto the substrate polymer. Exemplary spray parametersare discussed in detail below. Polymer coatings applied to plasmatreated surfaces should adhere more strongly, and be more likely towithstand the expansion step of implanting a medical device such as astent.

In certain embodiments, a surface of a stent can be selectively treatedwith a plasma. In particular, coating on regions subjected to highstrain during expansion and crimping is particularly susceptible tocracking, peeling, and delamination. In particular, surface regions ofbending elements 130, 140, and 150 undergo substantial deformationduring crimping and expansion. In some embodiments, selected surfaceregions of a polymer stent can be selectively plasma treated. In theseembodiments, selective plasma treatment can be performed by reducing orpreventing treatment of areas other than the selected regions. In oneembodiment, a mask or covering can be disposed over the stent thatallows treatment of selected regions and shields other regions fromtreatment. Such masks can be composed of stainless steel, aluminum,cobalt chromium alloys, titanium, niobium, tantalum, tungsten, orceramics such as alumina, zirconia, or tungsten carbide. In someembodiments, a mask can include one or more bands that mask or shieldstraight portions of struts with bending portions exposed to plasma.

In further embodiments, a polymer surface of an implantable medicaldevice can be treated with a plasma to ablate the polymer surface. Ingeneral, plasma ablation refers to removal of material from the polymersurface due to treatment of the plasma. Ablation of a surface with aplasma results in the breaking of weak covalent bonds in a polymer dueto the bombardment with high-energy particles. The ablation removesoutermost molecular layers of the substrate exposed to the plasma. Themolecular layers are sputtered off, or are reduced to such low molecularweight that they evaporate off, and can be removed by a vacuum. Becausethe chemistry of most layers of surface contamination is generallycomposed of organic compounds, plasma treatment can remove contaminantssuch as oil films or molding additives. It is expected that the plasmaablated surface is more uniformly clean and a more active polymersurface. Thus, in some embodiments, the plasma ablated surface hasincreased adhesion with a coating polymer.

Mechanical Surface Roughening

In several embodiments, mechanical methods may be used to increase thesurface roughness of the surface of a polymeric stent to increase thesurface area. The increase in surface roughness or surface area tends toincrease the adhesion of a coating disposed over the roughened surface.Embodiments of mechanical methods for roughening a polymer stent surfacemay include abrasive blasting of a polymer stent surface such as beadblasting and sand blasting, or immersion in agitated particle dispersionin a fluid (liquid or gas), but are not limited thereto.

A rough surface refers to a surface having ridges and projections on thesurface. A “smooth surface” refers to a surface that is continuous andeven. The roughness of a surface or deviation from a smooth surface canbe measured by roughness factor (rugosity) of a surface which is givenby the ratio:f _(r) =A _(r) /A _(g)where A_(r) is the real (true, actual) surface (interface) area andA_(g) is the geometric surface (interface) area free of ridges andprojections that cause the roughness. 1986, 58, 439 IUPAC Compendium ofChemical Terminology 2nd Edition (1997). A smooth surface corresponds toa mathematical representation of a surface, such as a cylindricalsurface of a tube. “Substantially smooth” refers to a surface that isfree or relatively free of ridges, projections, or deviations from, forexample, a mathematical surface such as a cylindrical surface. In thecase of a tube, the geometric surface area is the surface area of asection of a smooth cylindrical surface and the real surface area is theactual surface area of such a section taking into account deviationsfrom the smooth cylindrical surface due to ridges, projections, etc.Substantially smooth can refer to a surface having a roughness factortypical of a tube fabricated from extrusion.

Blasting Embodiments

Certain embodiments of the present invention include the use of abrasiveblasting to increase the roughness of a polymer stent surface. Abrasiveblasting refers generally to propelling particulate material athigh-velocity at a surface of a substrate in a manner than increases theroughness of the surface. Such methods can include sand blasting or beadblasting. In such embodiments, a stream of particles is directed at apolymer stent surface in a manner that etches the surface, thusincreases the surface roughness of at least a portion of the polymersurface. “Etching” refers to producing a regular or irregular pattern ona material by indentation or remove of material from the material'ssurface. The degree or roughening can be controlled by a several factorsincluding the particles size, particle velocity, density of particles inparticles stream, and the mass of the particles.

Abrasive blasting systems are known and commercially available. Anabrasive blasting system generally includes: the abrasive or particulatematter, an air compressor, and a blaster gun. The system generates apressurized abrasive gas stream from the blaster gun with abrasive mixedor dispersed therein. For abrading a small object, such as a stent, thesystem includes a fixture for holding the object during abrasivetreatment. The system additionally can include a collector, such as avacuum system, to gather up particulate material and material removedfrom the substrate. The pressurized gas can include gases including, butnot limited to, air, nitrogen, argon, carbon dioxide, or a combinationthereof. In other embodiments, the gas may include a solvent for thesurface polymer.

Various types of particulate matter may be used in embodiments of thepresent invention. Exemplary classes of materials include metals,metallic salts, ceramics, polymers, and combinations thereof Exemplarymaterials are provided below. As indicated above, the degree ofroughness imparted by the abrasive process can depend on the particlessize. It is expected that the scale of indentations and protrusionsimparted are similar to the particle size. Thus, the particle size ofthe abrasive material can be adjusted to obtain a desired degree ofroughness and length scale of indentations and protrusions.

In certain embodiments of abrasive treatment, a stent is mounted onstent support, such as a mandrel, which is supported by a fixture. Themandrel can be configured to allow uniform or near uniform exposure ofthe stent surface to the stream of abrasive. Additionally, the nozzleand stent can be configured to move relative to one another to maximizethe surface area of the stent abraded by the abrasive treatment. FIG. 3depicts an exemplary system 300 for abrasive treatment of a stent. Astent 302 is supported by mandrel including a cone member 304 and a conemember 306 with a wire 308 extending between the cone members. Aproximal end 302A of stent 302 is supported by cone member 304 and adistal end 302B of stent 302 is supported by cone member 306. One orboth of the cone support members are affixed to rotatable fixture (notshown) that allows rotation of stent 302 as shown by an arrow 310. Anozzle 312 propels stream of abrasive mixture 314 onto stent 302, asshown by an arrow 315. Additionally, nozzle 312 translates along theaxis of stent 302 as shown by an arrow 316.

Additionally, following the abrasive treatment, the stent can beprocessed to remove abrasive particulate matter adhered to the abradedsurface. In one embodiment, the stent can be treated, such as by dippingor spraying, with a fluid that is inert to the polymer surface of thestent. For example, the stent can be treated with an aqueous fluid or anorganic fluid that is a nonsolvent for the polymer. A pressurized gasstream free of abrasive material can also be used to remove adheredparticulate matter. In addition, adhered matter can also be removeddisposing the stent in a liquid such as water (e.g., deionized water) ora nonsolvent and sonicating the liquid.

In some embodiments, the particles can have a characteristic length,such as a diameter, between about 0.2 microns and about 15 microns. Itis believed that if the particles are small enough, treatment of asurface may not increase the surface roughness and may even polish thestent surface, i.e., make the surface smoother. The particles can becomposed of materials including, but not limited to, silicon, siliconcarbide, aluminum oxide, sodium chloride, sodium phosphate, bicarbonateof soda, calcium carbonate, irregular particles of glass, quartz,silicon carbide, tungsten carbide, alumina, zirconia, calcium salts,magnesium salts, tungsten, tungsten alloys, stainless steels, and cobaltchrome alloys. In certain embodiments the abrasive particles are high indensity and comprise metals and high density ceramics.

Exposing Stent Surface to Gas Mixed with Abrasive Material in a Chamber

Other embodiments of treating a polymeric surface of a stent with aparticle gas mixture can include disposed a stent in a chamber withabrasive material and inducing movement or flow of the particles toabrade the stent surface. In one exemplary embodiment, a stent is placedin a container along with abrasive particles and the container isagitated. In certain embodiments, the agitation occurs by shaking,vibrating, rotating, or generally moving the container in manner thatgenerates movement of the particles across the stent surface in a mannerthat abrades the stent surface. In an exemplary embodiment, an elongatecontainer, such as a cylindrical container, may be rotated about itscylindrical axis, or end over end. In some embodiments, the containermay be only partially filled with abrasive media, for example, ½, ⅔, or¾ filled by volume.

Fluidized Bed

In further embodiments, a polymer surface of a stent can be abraded byexposing the stent to an agitated particulate gaseous suspension. Anagitated particle suspension refers to a particulate matter that issuspended and undergoes constant movement. In some embodiments, a stentcan be supported within a chamber including the agitated suspension. Insome embodiments, an agitated particle suspension can be formed throughintroduction of pressurized gas into a vessel or container holding aparticulate medium. In such embodiments, the particulate medium presentin a vessel can exhibit properties characteristic of a fluid, such asthe ability to free-flow under gravity, or to pumped using fluid typetechnologies. In some embodiments, the agitated particle suspension is afluidized bed which refers to a bed of solid particles with a stream ofair or gas passing upward through the particles at a rate great enoughto set them in motion. The degree of abrasion can depend on the velocityof the particles, the flow rate of pressurized gas, the pressure of thegas, and the density of the particles in the vessel. The suspension haveless than 5 vol %, 20-30 vol %, 30-50 vol %, or greater than 50 vol % ofparticles.

An exemplary embodiment of abrasion of the polymeric surface of a stentis depicted in FIG. 4A. FIG. 4A depicts a stent 400 in a container 405containing particles 410. The embodiment of FIG. 4A is also similar to afluidized bed. A gas is blown into container 410, as shown by an arrow415, by a pump or a blower 420. The gas induces movement of particles410 which abrade the polymeric surface of stent 400. The gas can be asolvent vapor or a gas mixture including a solvent for the surfacepolymer and a nonsolvent for the surface polymer. It is believed thatthe solvent can facilitate etching of the surface, and thus, increasingthe surface roughness. Alternatively, the gas can be a nonsolvent forthe surface polymer such as air, nitrogen, oxygen, argon, etc.

Gas exits container 410 at air outlet 425, as shown by an arrow 430. Gascan be recirculated to pump or blower 420 through tube 440, as shown byarrows 435. Air outlet 425 can have a filter to prevent particles fromentering tube 440. Alternatively, the gas may not be recirculated.

Exposing Stent Surface to Liquid Abrasive Medium

Additional embodiments of abrading a polymeric surface of a stentinclude contacting a polymeric surface of a stent with a liquid medium.In some embodiments, the liquid medium can be mixed with abrasiveparticles, forming an abrasive liquid suspension. In certainembodiments, the liquid medium can include a solvent for the surfacepolymer that is capable of dissolving the surface polymer. In otherembodiments, the liquid medium can be a nonsolvent for the surfacepolymer that is not capable of dissolving the surface polymer. Anabrasive liquid suspension with a solvent, the surface can be modifiedby dissolving at least a portion of the surface polymer. The particlescan modify the polymeric surface by abrading the polymeric surface.Several embodiments of abrading a polymer surface of a stent with aliquid medium are analogous to the embodiments described above usinggas/particles mixtures.

Water Jet

In certain embodiments, a polymer surface of a stent can be abraded orroughened by a high-velocity, pressurized stream of liquid. In someembodiments, the stream of fluid can be a concentrated jet of liquid,free or substantially free of gas bubbles. The stream can be directedonto a polymer surface of a stent in a manner that increases the surfaceroughness of the stent. The degree of abrasion depends on factors suchas the velocity of the stream and the radial cross-section of thestream. The liquid can be water or an organic liquid. The organic liquidcan be solvent or a nonsolvent for the surface polymer. In furtherembodiments, the liquid stream can include an abrasive particulatematerial. Water jet cutting is known and used for cutting and abrasionof surface and can be adapted to abrasion of polymer stent surfaces withwater and other liquids.

A system for liquid abrasion of a polymer stent surface can include anozzle connected to a high-pressure pump. The liquid is then ejected outof the nozzle onto a polymer stent material by bombarding it with thestream of high-speed water. Abrasive materials can be mixed with thewater at or before the nozzle. An exemplary system for liquid abrasionof a polymer stent is similar to that depicted in FIG. 3. Nozzle 312 caneject a stream of fluid onto the surface of stent 302. In someembodiments, the nozzle can eject a pulsating jet of fluid onto thestent surface.

In additional embodiments, a polymer surface of a stent can be abradedor roughened by an atomized stream of liquid directed onto a surface ofa stent. An atomized stream of liquid is composed of fine droplets ofliquid mixed with a gas. In some embodiments, the atomized stream ofliquid can further include an abrasive material. Spray devices thatproduce a stream of atomized droplets are known and used for spraycoating of devices such as stents. A spray apparatus, such as EFD 780Sspray device with VALVEMATE 7040 control system (manufactured by EFDInc., East Providence, R.I.) is a spray device with an air-assistedexternal mixing atomizer. Such a spray device produces an atomizedstream from a mixture of liquid and gas.

In additional embodiments, a polymer surface of a stent can be abradedby exposing the stent to an agitated particulate liquid suspension. Insuch embodiments, stent can be disposed in a vessel containing a liquidparticles suspension. The stent can be supported on a fixture or allowedfree to translate through the suspension. The liquid particulatesuspension can be agitated in a number of ways. In one embodiment, thevessel can be agitated by shaking, vibrating, rotating, or generallymoving the container in manner that generates movement of the particlesacross the stent surface to abrade the stent surface. In otherembodiments, the liquid particle suspension can be agitated throughintroduction of pressurized gas into the vessel or container holdingsuspension. In another embodiment, the suspension can be stirred by amechanical mixer or ultrasonic mixing.

Brush

In some embodiments, a polymer stent surface can be roughened throughapplication of an abrasive member to a stent surface. In someembodiments, the abrasive member can be a brush. In such embodiments, abrush having metallic wire bristles or more generally bristles stiffenough to roughen the polymeric stent surface. Examples of brushesinclude, but are not limited to, brushes composed of arrays of metallicwires, ceramic wires, glass wires, wires with abrasive media affixed tothem, and wires of very hard polymers or reinforced polymers. In otherembodiments, an abrasive member can have a surface of sand paper oremery cloth.

In certain embodiments, a cylindrical brush can be drawn through thelumen of the stent so that the outside surface of the brush roughens theluminal surfaces and a portion of the sidewalls. A stent drawn throughthe inside of a hollow cylindrical brush so that the inside surface ofthe brush roughens the abluminal surface of the stent. The stent can beplaced on a mandrel and then pushed though the annulus.

In certain embodiments, a stent can be disposed on a rotatable supportwith a fixed cylindrical brush disposed within or around the outside ofthe stent. The luminal or abluminal surface and at least a portion ofthe sidewalls of the stent are roughened through rotation of the stentrelative to the brush. Alternatively, the brush can be rotated relativeto the stent. In further embodiments, the stent or brush can betranslated relative to one another. In an embodiment 450 as illustratedin FIG. 4B, the luminal surface of stent 460 is roughened by brush 455by rotating brush 455 in direction 462, and/or translating brush 455 indirection 464. In an additional embodiment 470 as illustrated by FIG.4C, the roughening of the abluminal surface of stent 480 by using brush475 occurs when brush 475 is rotated in direction 482 and/orsimultaneously translated in direction 484.

Surface Swelling/Etching

In further embodiments, the adhesion of coating to a polymer surface ofa stent can be improved through treatment of the polymer surface with asolvent or a mixture of solvents. Some embodiments of the treatment caninclude applying a solvent onto the polymer surface, followed by removalof at least some of the solvent. A coating may then be applied to thetreated surface that includes some of the solvent or a treated surfacethat free or substantially free of solvent. The roughness of the polymersurface increased by the treatment which enhances the adhesion of acoating layer applied to the treated surface. The polymer stent surfacemay be roughened by a swelling, dissolution or etching of a surfacepolymer, or a combination of both.

As is understood by persons of skill in the art, swelling of a polymeroccurs when a solvent in contact with a sample of the polymer diffusesinto the polymer. L. H. Sperling, Physical Polymer Science, 3^(rd) ed.,Wiley (2001). Thus, a swollen polymer sample includes solvent moleculesdispersed within the bulk of the polymer. Dissolution of the polymeroccurs when polymer molecules diffuse out of the swollen polymer intosolution.

“Solvent” for a given polymer can be defined as a substance capable ofdissolving or dispersing the polymer or capable of at least partiallydissolving or dispersing the polymer to form a uniformly dispersedmixture at the molecular- or ionic-size level. The solvent should becapable of dissolving at least 0.1 mg of the polymer in 1 ml of thesolvent, and more narrowly 0.5 mg in 1 ml at ambient temperature andambient pressure. A substance incapable or substantially incapable ofdissolving a polymer should be capable of dissolving only less than 0.1mg of the polymer in 1 ml of the non-solvent at ambient temperature andambient pressure, and more narrowly only less than 0.05 mg in 1 ml atambient temperature and ambient pressure. A substance incapable orsubstantially incapable of dissolving a given polymer is generallyreferred to as a nonsolvent for that polymer. A nonsolvent or a poorsolvent may be capable of swelling a polymer.

Solvents and nonsolvents for polymers can be found in standard texts(e.g., see Fuchs, in Polymer Handbook, 3rd Edition and Deasy,Microencapsulation and Related Drug Processes, 1984, Marcel Dekker,Inc., N.Y.). The ability of a polymer to swell and to dissolve in asolvent can be estimated using the Cohesive Energy Density Concept (CED)and related solubility parameter values as discussed by Deasy and can befound in detail in the article by Grulke in Polymer Handbook. Thus, aperson skilled in the art will be able to select a solvent that iscapable of swelling the surface polymer and is incapable orsubstantially incapable of dissolving the surface polymer.

Treating with Poor Solvent

In certain embodiments, a polymer stent surface is treated with asolvent. In some embodiments, the solvent is a nonsolvent or a poorsolvent that swells and dissolves little or none of the surface polymer.In other embodiments, the treatment solvent dissolves or etches thesurface polymer and swells the surface polymer.

In some embodiments, the solvent is applied to the surface in an amountsuch that there is a layer or film of solvent present on the surface. Insuch an embodiment, a layer of solvent may be present over all ormajority of the surface area of the stent to be treated. In theseembodiments, a solvent can be selected that exhibits a high degree ofwetting of the surface. “Wetting” refers to the degree to which a liquidmaintains contact with a surface. Poor wetting is indicated by liquidsbeading up on a surface and good wetting is indicated by a continuoussheet of liquid forming on the surface.

In some embodiments, the solvent may swell at least a portion of thesurface polymer. In an embodiment, the applied solvent may form aswollen of surface polymer over unswollen surface polymer. FIG. 5depicts a cross-section of a stent showing a solvent layer 500 over aswollen surface polymer layer 510. Swollen surface polymer layer 510 isover an unswollen surface polymer layer 520. In the case of a treatmentsolvent that dissolves surface polymer, layer 510 includes dissolvedsurface polymer. As indicated above, unswollen surface polymer 520 canbe a substrate of the stent. As shown, swollen surface polymer layer 510has a thickness Tse.

In such embodiments, the solvent is applied to the surface of thepolymer by methods such as spraying or dipping. In an exemplary treatingembodiment, the stent mounted on a rotatable support is rotated andtranslated under a spray nozzle that sprays the solvent onto the stentsurface. The stent may be passed 1-5 times or more than 5 times underthe spray nozzle. In other embodiments, the stent can be disposed in asolvent bath for a period of time, for example 1-5 seconds, 5-30seconds, or more than 30 seconds. The solvent layer can be allowed toremain on the surface for a period of time, for example, 1-5 seconds,5-30 seconds, or more than 30 seconds.

Following application and wetting of the surface polymer with thesolvent, the treatment method includes removal of some or all of thesolvent from the stent surface. In some embodiments, the all orsubstantially all of the solvent layer is removed while leaving theswollen polymer layer. In other embodiments, the solvent layer and allor substantially all of the solvent in the swollen polymer is removed.

In general, it is believed that a rapid removal of the solvent mayfacilitate roughening of the surface polymer and thus adhesionimprovement. In some embodiments, the solvent can be removed by blowinggas stream over the stent surface. The gas stream can be air, nitrogen,oxygen, argon, or other gas. The gas stream can be room temperature air,i.e., 20-30° C. Alternatively, the gas stream can be heated to atemperature between 30-50° C. or greater than 50° C.

In other embodiments, the solvent can be removed by allowing the solventto evaporate without assistance of a gas stream at or near roomtemperature for a period of time. The drying period may be less than 10minutes, 10-20 minutes, 20-30 minutes, or greater than 30 minutes. Insome embodiments, a high volatile solvent is used with a relatively highevaporation rate. Such a solvent may be one that can evaporatecompletely from the surface of the stent in less than 5-20 minutes. Inother embodiments, the solvent can be removed by allowing the solvent toevaporate without assistance of a gas stream above room temperature, forexample, between 30-50° C. or greater than 50° C. In some embodiments,the treated surface has increased roughness has increased adhesion witha coating polymer.

After removal of some or all of the solvent, the polymer surface of thestent can be coated with a polymer that can include a drug. A coatingmaterial including a coating polymer dissolved in a coating solvent anda drug mixed with the coating solvent. The coating material can beapplied by methods such as spraying or dipping followed by removal ofcoating solvent to form the coating over the surface polymer.

In some embodiments, the coating material can be applied over thepolymer surface having at least some of the solvent layer. In otherembodiments, the coating material can be applied to the polymer surfacethat is free or substantially free of the solvent layer over the swelledregion. Additionally, the coating material is applied to a surfacepolymer free or substantially free of the solvent layer.

In an exemplary embodiment, the surface polymer is PDLA of a stentformed from PLLA. Exemplary treatment solvents include acetone,methylene chloride, tetrahydrofuran (THF), cyclohexane, chloroform,dimethyl chloroform, and combinations thereof. An exemplary weak or poorsolvent treatment solvent is acetone which tends to swell, but notdissolve PLLA. Exemplary good solvent that swells and dissolves oretches PLLA include chloroform and dimethyl chloroform. Cyclohexane is aweaker solvent than THF. A solvent intermediate between weak and strongsolvents is THF. An exemplary coating polymer can be PDLA dissolved inacetone coating solvent.

Treatment with a Mixture of Solvents

In further embodiments, the treatment solvent can be solvent system thatincludes a mixture of two or more solvents. In some of theseembodiments, the solvent system can include solvents that are ofdifferent strengths with respect to the surface polymer. The solventsystem can include a weak solvent and a strong solvent. The weak solventmay swell, but not dissolve the surface polymer while the strong solventdissolves and swells the surface polymer. An exemplary solvent systemincludes acetone and chloroform. Additional solvents include IPA andchloroform, but are not limited thereto.

In other embodiments, the solvent system can include a solvent having ahigher evaporation rate or of a greater volatility than another solventin the solvent system. Evaporation rate refers to the mass of materialthat evaporates from a surface per unit time (e.g., 3 grams per squaremeter per hour). A dimensionless evaporation rate can be defined as therate at which a material will vaporize (evaporate, change from liquid tovapor) compared to the rate of vaporization of a specific knownmaterial. The general reference material for evaporation rates isn-butyl acetate. The ratios for some exemplarily solvents are asfollows: acetone (5.6), chloroform (11.6), tetrahydrofuran (8.0),cyclohexane (2.6), ethanol (2.7), methylene chloride (27.5),dimethylacetamide (<0.17), dimethyl sulfoxide (4.3). In someembodiments, the solvent system includes two solvents with a ratio ofevaporation rates of 1-1.5, 1.5-2, 2-5, or greater than 5. Exemplarysolvent systems with ratio of evaporation rates includechloroform/acetone (2.1), tetrahydrofuran/acetone (1.4),acetone/cyclohexane (2.2), methylene chloride/acetone (4.9), methylenechloride/ethanol (10.2), but are not limited thereto.

In additional embodiments, the solvents of the solvent system aremiscible. Alternatively, two or more of the solvents are immiscible.

Treatment with a solvent system with solvent having different strengths,evaporation rates, or both facilitates increasing the roughness of thepolymer surface of the stent.

Phase Inversion

In some embodiments, a phase inversion method is used to roughen apolymer surface of a stent to improve adhesion of a coating. In suchembodiments, a solvent capable of dissolving the surface polymer isapplied to a stent from a solvent layer on the surface, as describedabove. Additionally, the applied solvent is miscible with phaseinversion fluid. In some embodiments, the phase inversion fluid iswater. Next, the stent is exposed to the phase inversion fluid, therebycausing the dissolved surface polymer in the solvent surface layer toprecipitate out. The exposure to water can include exposure to a gaseousenvironment with a high percentage of the phase inversion fluid. Forexample, the stent can be exposure to high humidity environment, forexample, at least 70%, 80%, 90%, or 100% humidity. In other embodiments,the stent can be dipped in or sprayed with the phase inversion fluid inliquid form The phase inversion fluid may also be a non-polarnon-solvent.

In an exemplary embodiment, the surface polymer is PLLA. Exemplarysolvents useful in the phase inversion method include, but are notlimited to, dimethylacetamide (DMAC), dimethyl sulfoxide (DMSO),hexafluoroisopropanol and 2,2,2-trifluoroethanol. In an embodiment, aPLA stent is sprayed with DMSO and then air with 100% humidity isdirected to the treated surface. The resulting treated surface shouldincrease the adherence of a later added coating layer. In anotherembodiment, a PLLA stent is dipped briefly in DMAC and then dipped intowater, resulting in a roughened surface that should increase theadherence of a coating layer. Any combination of dipping or sprayingprocedures may be used to treat the polymer surface.

Coating Method

In an exemplary embodiment of a coating procedure, a treated stenthaving a substrate of PLLA is coated with PDLA. The coating material isPDLA dissolved in acetone. The weight fraction of solvent in coatingmaterial can be greater than 50%, 70%, 80%, 95%, or more narrowly, 97%.The spray nozzle forms an atomized stream of coating material forapplication on the stent. The spray nozzle temperature or atomizationtemperature can be between about 15° C. and 30° C. Atomization pressurecan be between 5.5 psi and 7 psi. A temperature of heated air from aheat nozzle directed at the stent can be between 38° C. and 40° C. Theair pressure of the nozzle can be between 18 psi and 22 psi. The syringepump rate can be between 2 ml/hr and 6 ml/hr.

Adhesion Promoting Layer

Embodiments of the present invention include an implantable medicaldevice including an adhesion promoting layer between a therapeutic layerand polymer surface of the device. In some embodiment, the promotinglayer includes a block copolymer with an outer block and an anchorblock. In some embodiments, the outer block, the anchor block, or bothcan be bioabsorbable polymers. In addition, the anchor block is misciblewith the surface polymer and the outer block is miscible with thetherapeutic layer. Additionally, the therapeutic layer may contain anactive agent or drug mixed or dispersed within a polymer.

In other embodiments, the adhesion promoting layer includes a copolymerhaving some units that are miscible in the surface polymer and some thatare miscible in the therapeutic layer.

In such embodiments, the block copolymer adhesion promoting layer canhave more than one outer block and more than one anchor block. In oneembodiment, the block copolymer can have an outer block on one end andan anchor block at another end. In another embodiment, the blockcopolymer can have an outer block between two anchor blocks or anchorblock between two outer blocks.

FIG. 6A depicts a cross-section of a substrate 640 of a stent with anadhesion promoting layer 650 disposed over substrate 640. A therapeuticlayer 660 is disposed over adhesion promoting layer 650. Therapeuticlayer 660 includes a drug 670 dispersed within a polymer 680. Adhesionpromoting layer 650 improves the adhesion of drug-polymer layer 660 tosubstrate 640.

As indicated above, the anchor block of the block copolymer of theadhesion promoting layer is miscible with the surface polymer. In oneembodiment, the anchor block can have the same chemical composition asthe surface polymer. Alternatively, the anchor block can have a chemicalcomposition different from the surface polymer, but similar enough sothat the anchor block is miscible with the surface polymer. In anexemplary embodiment, the block copolymer of the adhesion promotinglayer can have a PLLA anchor block and be disposed over a PLLA surface,which can be the surface of a PLLA stent substrate.

In some embodiments, the adhesion promoting layer can be applied to apolymer surface so that at least some of the outer blocks of the blockcopolymers are mixed within the therapeutic layer. Additionally, anchorblocks can be mixed within the surface polymer. The anchor blocks of theblock copolymer act as a compatibilizer that strengthens the bondbetween the adhesion promoting layer and the surface polymer. Similarly,the outer blocks of the block copolymer act as a compatibilizer thatstrengthens the bond between the adhesion promoting layer and thetherapeutic layer.

FIG. 6B depicts a cross-section of a stent surface with an adhesionpromoting layer 610 over a substrate 600. Adhesion promoting layer 610can be applied to form an interfacial region 642 which can includeanchor blocks mixed with substrate polymer. A thickness Ti ofinterfacial region 642 can be varied depending on coating applicationprocessing parameters

The enhanced adhesion can allow the use of a tough, high fractureresistant coating that may otherwise have poor adhesion to a polymersubstrate of a device. The polymer material for a substrate of a device,such as a stent, may be selected primarily on the basis of strength andstiffness so that the stent substrate can provide support for a lumen.Such substrate polymers tend to be crystalline or semi-crystallinepolymers that are glassy or have a Tg above body temperature. Suchglassy substrate polymers include PLLA.

In exemplary embodiments, the molecular weight of the outer blocks canbe between 20 kg/mol and 150 kg/mol, or greater than 150 kg/mol. Inexemplary embodiments, the molecular weight of the anchor blocks can bebetween 20 kg/mol and 150 kg/mol, or greater than 150 kg/mol. Therelative weight percent of the outer blocks and the anchor blocks can bebetween 1:5 and 5:1.

Embodiments of the block copolymers disclosed herein can be formed bysolution-based polymerization. Other methods of forming the blockcopolymers are also possible, such as, without limitation, melt phasepolymerization.

The block copolymer adhesion promoting layer may be formed over animplantable medical device, such as a stent, by applying coatingmaterial to a polymer surface of the device. The coating material can bea solution including the block copolymer. The adhesion promoting layermay be applied to the stent by immersing the device in the coatingmaterial, by spraying the composition onto the device, or by othermethods known in the art. The solvent in the solution is removed,leaving on the device surfaces the adhesion promoting layer.

In some embodiments, the solvent of the adhesion promoting layer is alsoa solvent for the surface polymer on which the adhesion promoting layeris applied.

Due to dissolution or swelling of a portion of the surface polymerduring application of coating material, the adhesion promoting layernear the surface of the surface polymer includes dissolved surfacepolymer in addition to the block copolymer from the adhesion promotinglayer. It is believed that upon removal of the solvent, an interfacialregion, as depicted in FIG. 6B, is formed that includes anchor blocks ofthe block copolymer adhesion promoting layer mixed with surface polymer.This interfacial region can be formed due to the miscibility of thesurface polymer with the anchor blocks.

FIG. 6C depicts a cross-section of a stent showing an adhesion promotinglayer 602 over a swollen surface polymer layer 612. Swollen surfacepolymer layer 612 is over un-swollen surface polymer substrate 620. Asshown, swollen surface polymer layer 612 has a thickness Ts. Due toswelling of the surface polymer in swollen polymer layer 612, it isbelieved that anchor blocks of the block copolymer in adhesion promotinglayer 602 penetrate into or mix with the surface polymer in swollenpolymer layer 612 prior to removal of the solvent. Upon removal of thesolvent, a coating layer is formed over substrate 620. In someembodiments, a polymeric surface layer can be pretreated with a solventthat dissolves or swells the surface polymer prior to applying anadhesion promoting layer. Following pretreatment, the adhesion promotinglayer can be applied over the pretreated surface.

In other embodiments, a therapeutic layer is applied over the adhesionpromoting layer that has been applied to a polymeric surface. Atherapeutic polymer layer can then be formed over the block copolymeradhesion promoting layer. A coating material includes a therapeuticcoating polymer dissolved in a solvent and a drug. FIG. 6D depicts adrug layer 652 over an adhesion promoting layer 630. Drug layer 652includes a drug 662 mixed or dispersed within a polymer 672. A firstinterfacial layer 642 of thickness Ti₁, discussed above, includes anchorblocks and the surface polymer 600. A second interfacial layer 645 ofthickness Ti₂ is located between drug layer 652 and adhesion promotinglayer 630. This interfacial layer may include polymer from the druglayer 652 and outer blocks from adhesion promoting layer 630. Thus,improved adhesion of drug layer 652 is accomplished by strengthening thebond between drug layer 652 and adhesion promoting layer 630, as well asstrengthening the bond between adhesion promoting layer 630 and surfacepolymer 600.

In exemplary embodiments, a stent substrate of scaffolding is PLLA andthe therapeutic layer is PDLA. In such embodiments, the adhesion coatinglayer can include, but is not limited to PLLA-b-PDLA, PLLA-co-PDLA andPLLA-co-PLGA. Additionally, polyethylene (PEG) is compatible with PLLAand PPG (polypropylene glycol) is compatible with PDLA. Thus, theadhesion promoting layer can include PDLA-b-PEG and PPG-b-PEG.

In exemplary embodiments, the adhesion promoting layer is about 0.05 μmto about 5 μm. In other embodiments, the thickness is from about 0.1 μmto 1 μm, 0.1 μm to 3 μm, or 0.1 μm to 5 μm.

In general, representative examples of polymers that may be used tofabricated a substrate of and coatings for an implantable deviceinclude, but are not limited to, poly(N-acetylglucosamine) (Chitin),Chitosan, poly(hydroxyvalerate), poly(D,L-lactide-co-glycolide),poly(hydroxybutyrate), poly(hydroxybutyrate-co-valerate),polyorthoester, polyanhydride, poly(glycolic acid), poly(glycolide),poly(L-lactic acid), poly(L-lactide), poly(D,L-lactic acid),poly(L-lactide-co-glycolide); poly(D,L-lactide), poly(caprolactone),poly(trimethylene carbonate), polyethylene amide, polyethylene acrylate,poly(glycolic acid-co-trimethylene carbonate), co-poly(ether-esters)(e.g. PEO/PLA), polyphosphazenes, biomolecules (such as fibrin,fibrinogen, cellulose, starch, collagen and hyaluronic acid),polyurethanes, silicones, polyesters, polyolefins, polyisobutylene andethylene-alphaolefin copolymers, acrylic polymers and copolymers otherthan polyacrylates, vinyl halide polymers and copolymers (such aspolyvinyl chloride), polyvinyl ethers (such as polyvinyl methyl ether),polyvinylidene halides (such as polyvinylidene chloride),polyacrylonitrile, polyvinyl ketones, polyvinyl aromatics (such aspolystyrene), polyvinyl esters (such as polyvinyl acetate),acrylonitrile-styrene copolymers, ABS resins, polyamides (such as Nylon66 and polycaprolactam), polycarbonates, polyoxymethylenes, polyimides,polyethers, polyurethanes, rayon, rayon-triacetate, cellulose, celluloseacetate, cellulose butyrate, cellulose acetate butyrate, cellophane,cellulose nitrate, cellulose propionate, cellulose ethers, andcarboxymethyl cellulose.

Additional representative examples of polymers that may be especiallywell suited for use in embodiments of the present invention includeethylene vinyl alcohol copolymer (commonly known by the generic nameEVOH or by the trade name EVAL), poly(butyl methacrylate),poly(vinylidene fluoride-co-hexafluoropropylene) (e.g., SOLEF 21508,available from Solvay Solexis PVDF, Thorofare, N.J.), polyvinylidenefluoride (otherwise known as KYNAR, available from ATOFINA Chemicals,Philadelphia, Pa.), ethylene-vinyl acetate copolymers, and polyethyleneglycol.

For the purposes of the present invention, the following terms anddefinitions apply:

For the purposes of the present invention, the following terms anddefinitions apply:

Drugs or therapeutic active agent(s) can include anti-inflammatories,antiproliferatives, and other bioactive agents.

An antiproliferative agent can be a natural proteineous agent such as acytotoxin or a synthetic molecule. Preferably, the active agents includeantiproliferative substances such as actinomycin D, or derivatives andanalogs thereof (manufactured by Sigma-Aldrich 1001 West Saint PaulAvenue, Milwaukee, Wis. 53233; or COSMEGEN available from Merck)(synonyms of actinomycin D include dactinomycin, actinomycin IV,actinomycin I₁, actinomycin X₁, and actinomycin C₁), all taxoids such astaxols, docetaxel, and paclitaxel, paclitaxel derivatives, all olimusdrugs such as macrolide antibiotics, rapamycin, everolimus, structuralderivatives and functional analogues of rapamycin, structuralderivatives and functional analogues of everolimus, FKBP-12 mediatedmTOR inhibitors, biolimus, perfenidone, prodrugs thereof, co-drugsthereof, and combinations thereof Representative rapamycin derivativesinclude 40-O-(3-hydroxy)propyl-rapamycin,40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, or 40-O-tetrazole-rapamycin,40-epi-(N1-tetrazolyl)-rapamycin (ABT-578 manufactured by AbbottLaboratories, Abbott Park, Ill.), Biolimus A9 (Biosensors International,Singapore), deforolimus, AP23572 (Ariad Pharmaceuticals), prodrugsthereof, co-drugs thereof, and combinations thereof In one embodiment,the anti-proliferative agent is everolimus.

An anti-inflammatory drug can be a steroidal anti-inflammatory agent, anonsteroidal anti-inflammatory agent, or a combination thereof In someembodiments, anti-inflammatory drugs include, but are not limited to,alclofenac, alclometasone dipropionate, algestone acetonide, alphaamylase, amcinafal, amcinafide, amfenac sodium, amiprilosehydrochloride, anakinra, anirolac, anitrazafen, apazone, balsalazidedisodium, bendazac, benoxaprofen, benzydamine hydrochloride, bromelains,broperamole, budesonide, carprofen, cicloprofen, cintazone, cliprofen,clobetsol, clobetasol propionate, clobetasone butyrate, clopirac,cloticasone propionate, cormethasone acetate, cortodoxone, deflazacort,desonide, desoximetasone, dexamethasone, dexamethasone acetate,dexamethasone dipropionate, diclofenac potassium, diclofenac sodium,diflorasone diacetate, diflumidone sodium, diflunisal, difluprednate,diftalone, dimethyl sulfoxide, drocinonide, endrysone, enlimomab,enolicam sodium, epirizole, etodolac, etofenamate, felbinac, fenamole,fenbufen, fenclofenac, fenclorac, fendosal, fenpipalone, fentiazac,flazalone, fluazacort, flufenamic acid, flumizole, flunisolide acetate,flunixin, flunixin meglumine, fluocortin butyl, fluorometholone acetate,fluquazone, flurbiprofen, fluretofen, fluticasone propionate,furaprofen, furobufen, halcinonide, halobetasol propionate, halopredoneacetate, ibufenac, ibuprofen, ibuprofen aluminum, ibuprofen piconol,ilonidap, indomethacin, indomethacin sodium, indoprofen, indoxole,intrazole, isoflupredone acetate, isoxepac, isoxicam, ketoprofen,lofemizole hydrochloride, lomoxicam, loteprednol etabonate,meclofenamate sodium, meclofenamic acid, meclorisone dibutyrate,mefenamic acid, mesalamine, meseclazone, methylprednisolone suleptanate,momiflumate, nabumetone, naproxen, naproxen sodium, naproxol, nimazone,olsalazine sodium, orgotein, orpanoxin, oxaprozin, oxyphenbutazone,paranyline hydrochloride, pentosan polysulfate sodium, phenbutazonesodium glycerate, pirfenidone, piroxicam, piroxicam cinnamate, piroxicamolamine, pirprofen, prednazate, prifelone, prodolic acid, proquazone,proxazole, proxazole citrate, rimexolone, romazarit, salcolex,salnacedin, salsalate, sanguinarium chloride, seclazone, sermetacin,sudoxicam, sulindac, suprofen, talmetacin, talniflumate, talosalate,tebufelone, tenidap, tenidap sodium, tenoxicam, tesicam, tesimide,tetrydamine, tiopinac, tixocortol pivalate, tolmetin, tolmetin sodium,triclonide, triflumidate, zidometacin, zomepirac sodium, aspirin(acetylsalicylic acid), salicylic acid, corticosteroids,glucocorticoids, tacrolimus, pimecorlimus, prodrugs thereof, co-drugsthereof, and combinations thereof In one embodiment, theanti-inflammatory agent is dexamethasone.

Alternatively, the anti-inflammatory may be a biological inhibitor ofproinflammatory signaling molecules. Anti-inflammatory biological agentsinclude antibodies to such biological inflammatory signaling molecules.

In addition, drugs or active can be other than antiproliferative agentsor anti-inflammatory agents. These active agents can be any agent whichis a therapeutic, prophylactic, or a diagnostic agent. In someembodiments, such agents may be used in combination withantiproliferative or anti-inflammatory agents. These agents can alsohave anti-proliferative and/or anti-inflammatory properties or can haveother properties such as antineoplastic, antiplatelet, anti-coagulant,anti-fibrin, antithrombonic, antimitotic, antibiotic, antiallergic,antioxidant, and cystostatic agents. Examples of suitable therapeuticand prophylactic agents include synthetic inorganic and organiccompounds, proteins and peptides, polysaccharides and other sugars,lipids, and DNA and RNA nucleic acid sequences having therapeutic,prophylactic or diagnostic activities. Nucleic acid sequences includegenes, antisense molecules which bind to complementary DNA to inhibittranscription, and ribozymes. Some other examples of other bioactiveagents include antibodies, receptor ligands, enzymes, adhesion peptides,blood clotting factors, inhibitors or clot dissolving agents such asstreptokinase and tissue plasminogen activator, antigens forimmunization, hormones and growth factors, oligonucleotides such asantisense oligonucleotides and ribozymes and retroviral vectors for usein gene therapy. Examples of antineoplastics and/or antimitotics includemethotrexate, azathioprine, vincristine, vinblastine, fluorouracil,doxorubicin hydrochloride (e.g. Adriamycin® from Pharmacia & Upjohn,Peapack N.J.), and mitomycin (e.g. Mutamycin® from Bristol-Myers SquibbCo., Stamford, Conn.). Examples of such antiplatelets, anticoagulants,antifibrin, and antithrombins include sodium heparin, low molecularweight heparins, heparinoids, hirudin, argatroban, forskolin, vapiprost,prostacyclin and prostacyclin analogues, dextran,D-phe-pro-arg-chloromethylketone (synthetic antithrombin), dipyridamole,glycoprotein IIb/IIIa platelet membrane receptor antagonist antibody,recombinant hirudin, thrombin inhibitors such as Angiomax a (Biogen,Inc., Cambridge, Mass.), calcium channel blockers (such as nifedipine),colchicine, fibroblast growth factor (FGF) antagonists, fish oil (omega3-fatty acid), histamine antagonists, lovastatin (an inhibitor ofHMG-CoA reductase, a cholesterol lowering drug, brand name Mevacor® fromMerck & Co., Inc., Whitehouse Station, N.J.), monoclonal antibodies(such as those specific for Platelet-Derived Growth Factor (PDGF)receptors), nitroprusside, phosphodiesterase inhibitors, prostaglandininhibitors, suramin, serotonin blockers, steroids, thioproteaseinhibitors, triazolopyrimidine (a PDGF antagonist), nitric oxide ornitric oxide donors, super oxide dismutases, super oxide dismutasemimetic, 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO),estradiol, anticancer agents, dietary supplements such as variousvitamins, and a combination thereof Examples of such cytostaticsubstance include angiopeptin, angiotensin converting enzyme inhibitorssuch as captopril (e.g. Capoten® and Capozide® from Bristol-Myers SquibbCo., Stamford, Conn.), cilazapril or lisinopril (e.g. Prinivil® andPrinzide® from Merck & Co., Inc., Whitehouse Station, N.J.). An exampleof an antiallergic agent is permirolast potassium. Other therapeuticsubstances or agents which may be appropriate include alpha-interferon,and genetically engineered epithelial cells. The foregoing substancesare listed by way of example and are not meant to be limiting.

Other bioactive agents may include antiinfectives such as antiviralagents; analgesics and analgesic combinations; anorexics;antihelmintics; antiarthritics, antiasthmatic agents; anticonvulsants;antidepressants; antidiuretic agents; antidiarrheals; antihistamines;antimigrain preparations; antinauseants; antiparkinsonism drugs;antipruritics; antipsychotics; antipyretics; antispasmodics;anticholinergics; sympathomimetics; xanthine derivatives; cardiovascularpreparations including calcium channel blockers and beta-blockers suchas pindolol and antiarrhythmics; antihypertensives; diuretics;vasodilators including general coronary; peripheral and cerebral;central nervous system stimulants; cough and cold preparations,including decongestants; hypnotics; immunosuppressives; musclerelaxants; parasympatholytics; psychostimulants; sedatives;tranquilizers; naturally derived or genetically engineered lipoproteins;and restenoic reducing agents. Other active agents which are currentlyavailable or that may be developed in the future are equally applicable.

EXAMPLES

The examples set forth below are for illustrative purposes only and arein no way meant to limit the invention. The following examples are givento aid in understanding the invention, but it is to be understood thatthe invention is not limited to the particular materials or proceduresof examples.

Example 1 Plasma Treatments

Poly(L-lactide) stents, 12 mm long from Bioabsorbable Vascular Solutions(BVS) are placed onto stainless steel wire mandrels. These mandrels areplaced into a Teflon fixture which holds the wires horizontally. Thisfixture with multiple stents is placed into a March Plasma C-SeriesPlasma Treater (St. Petersburg, Fla.). Using oxygen as the working gas,the stents are exposed to plasma conditions of 200 watts, approximately1 liter/minute oxygen flow rate at a pressure of 100 milli-torr for 150seconds. After removal from the plasma chamber, the stents may be coatedwith a drug reservoir layer within 12 hours.

Examples 2, 3 Mechanical Roughening Example 2

A 12 mm long poly(L-lactide) in-house stent is mounted on a mandrelcomposed of a central stainless steel wire on which are slid two conesvia holes in the cones. The cones point inwards and are of such adiameter to hold the stent at its distal and proximal ends. This mandrelis mounted in an apparatus to rotate the stent. A sand blastingapparatus, using compressed nitrogen gas is used to direct sodiumchloride particles at the stent while the stent rotates. Thesandblasting nozzle translates along the length of the stent. Aftersurface roughening, the stent is gently sonicated in deionized water toremove any adhered or embedded sodium chloride, followed by drying in avacuum oven or a desiccator.

Example 3

In another example, a 12 mm polylactide in-house is placed in a 20 mlglass vial. The vial is half filled with tungsten powder with an averagesize of 2 microns (Specialty Chemical Group LLC, Akron Ohio). The vialis rotated end over end at a speed of 30 rpm for 10 minutes.

Example 4 Roughening Using Solvents

A 12 mm poly(L-lactide) in-house stent is mounted in a spray systemwhich both translates and rotates the stent. Methylene chloride issprayed at the stent in a series of passes at high enough of a flux forliquid methylene chloride to be present on the stent surface, followedby in process drying with room temperature air for 10 seconds. Afterthree passes, the stent is allowed to air dry for 30 minutes beforeapplication of the drug reservoir layer.

Example 5 Adhesion Promoting Layer

A PLLA-b-PDLA polymer is synthesized via ring opening polymerizationusing 1-dodecanol as the initiator with a stannous octoate catalyst.This may be carried out in a toluene solvent, in an argon atmosphere ata temperature of 110° C. D,L-lactide monomer may be added first. Afterthe first monomer is consumed, the L-lactide is added and allowed topolymerize. The polymer is isolated by precipitation into methanolfollowed by drying in vacuo. The appropriate choice of catalyst/monomerstoichiometry will result in a poly(D,L-lactide-b-L-lactide) with Mw of80K and 50/50 monomer ratio by weight. This adhesion promoting polymeris applied to a 12 mm poly(L-lactide) in-house stent as a 2% (w/w)solution in chloroform. The stent is rotated at a speed of roughly 200rpm while passing longitudinally under the spray nozzle, followed by adrying procedure under an air stream at 40° C. for 10 seconds. Thecoating is applied as a series of spray passes with approximately 10 μgof coating applied per pass. Any remaining solvent is removed by ovendrying at 50° C. for one hour resulting in 100 μg of apoly(D,L-lactide-b-L-lactide) adhesion promoting polymer.

While particular embodiments of the present invention have been shownand described, it will be obvious to those skilled in the art thatchanges and modifications can be made without departing from thisinvention in its broader aspects. Therefore, the appended claims are toencompass within their scope all such changes and modifications as fallwithin the true spirit and scope of this invention.

What is claimed is:
 1. A method of improving the adhesion of a polymercoating layer to a stent surface comprising: Providing a stent formedfrom a substrate polymer; Treating a polymer surface of the stent with afluid, wherein the treating increases the roughness of the polymersurface; and Forming a coating comprising a coating polymer on thetreated stent surface, the increased surface roughness enhancing theadhesion of the coating polymer to the stent surface, wherein the fluidcomprises a solvent capable of dissolving the substrate polymer andabsorbing moisture at the surface of the stent, wherein the treatingcomprises applying the fluid to the surface of the polymer which atleast partially dissolves the polymer and exposing the treated stent toa phase inversion fluid to induce phase inversion, wherein the phaseinversion fluid is water or an organic non-polar non-solvent that doesnot substantially dissolve the surface polymer, wherein the phaseinversion fluid causes the dissolved surface polymer in the fluid toprecipitate out of solution and causes the roughness of the stentsurface to increase due to precipitation of the dissolved polymerinduced by phase inversion.
 2. The method of claim 1, wherein the fluidcomprises a solvent selected from the group consisting of acetone,methyl chloride, methylene chloride, chloroform, tetrahydrofuran, anddimethyl chloroform.
 3. The method of claim 1, wherein the treatingcomprises forming a layer of the fluid over the surface of the stent andremoving the layer of fluid by application of heat to the fluid layer.4. The method of claim 1, wherein the substrate polymer is PLLA and thefluid is a mixture comprising acetone and chloroform.
 5. The method ofclaim 1, wherein the substrate polymer is PLLA and the solvent isselected from the group consisting of DMAC, DMSO, andhexafluoroisopropanol, 2,2,2-trifluoroethanol.